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A Value-Based Approach To The Use Of PARP Inhibitors in Ovarian Cancer

A group of Duke Cancer Institute gynecologic oncologists, led by Andrew Berchuck, MD, are advising, in a perspectives article in the Journal of Clinical Oncology, that an evidence- and biomarker guided strategy-offers the best value-based approach to the use of oral PARP inhibitor drugs as maintenance therapy after patients with recurrent ovarian cancer have responded to conventional platinum-based chemotherapy.

Poly ADP-ribose polymerase (PARP) inhibitors are a type of drug that works by preventing base excision repair of DNA in cancer cells. PARP inhibitors enhance the accumulation of DNA strand breaks and promote genomic instability and death of cancer cells that also have already lost double stranded DNA repair due to mutations in BRCA1/BRCA2 or other genes in the homologous recombination (HR) pathway.

Investigators in the 2016 NOVA clinical study of the PARP inhibitor niraparib concluded that “among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of germ line BRCA1/2 mutations or HRD status, with moderate bone marrow toxicity.” This finding led to the FDA granting the drug breakthrough status in March 2017 as a maintenance therapy for all patients who had shown a partial or complete response to platinum-based chemotherapy rather than as a precision oncology therapy guided by complementary diagnostic tests for BRCA1/2 mutations and other HR pathway defects.

“Maintenance niraparib treatment delayed recurrence by an impressive 15 months on average for cases with BRCA1/BRCA2 mutations, but there was only a three month delay in those lacking these molecular alterations in their cancers,” explained Berchuck. “Furthermore, there is no evidence that delaying the next recurrence with maintenance niraparib therapy increases how long a patient will eventually live.”

In view of this, Berchuck and gynecologic oncologists Angeles Secord, MD, Hayley Moss, MD, MBA, and Laura J. Havrilesky, MD, MHSc, co-authors of the article, wrote that they “are not convinced that the data justify a paradigm shift from precision therapy to one size fits all.”

“The most compelling argument for using predictive tests to select patients for maintenance PARP inhibitor therapy may be their high cost,” they wrote, pointing to an approximate cost of $14,000 per month, although a significant fraction of patients having dose reductions that reduce that cost. They acknowledged that “in the wake of FDA approval, oncologists will believe that they have some obligation to discuss this therapy with all patients.” However, they pointed out that “on the basis of existing studies, it seems probable that evolution of a value-based approach to the use of PARP inhibitors in ovarian cancer will be facilitated by BRCA1/2 and HR pathway mutations and genomic instability tests that predict the efficacy of these drugs.”

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